David T. Durack

Metabolic fate of L-arginine in relation to microbiostatic capability of murine macrophages.

L-arginine is required for the fungistatic action of murine macrophages in vitro. To further investigate this requirement, L-arginine metabolism by macrophages was measured under conditions where fungistasis either succeeded or failed. Macrophage fungistasis correlated with metabolism of L-arginine to citrulline, nitrite, and nitrate. The metabolic rate was dependent on extracellular L-arginine concentration, reaching a maximum of 67 nmol nitrite/h per mg protein. It accounted for one-third of arginine consumed by fungistatic macrophages. Equimolar amounts of citrulline and total nitrite plus nitrate accumulated in medium. This was consistent with the hypothesis that one of the equivalent guanidino nitrogens of L-arginine was oxidized to both nitrite and nitrate leaving L-citrulline as the amino acid reaction product. The analogue, NG-mono-methyl-L-arginine, selectively inhibited nitrogen oxidation and it was shown previously that it inhibited fungistatic capability. Resident macrophages were not fungistatic and their nitrogen oxidation was low. Once macrophages began producing nitrite/nitrate, protein synthesis was not required during the next 8 h for either fungistasis or nitrogen oxidation. Two-thirds of L-arginine consumption was due to macrophage arginase yielding L-ornithine and urea, which accumulated in medium. This activity was dissociated from macrophage fungistasis. Nitrogen oxidation metabolism by macrophages is linked to a mechanism that inhibits proliferation of fungi. This may involve synthesis of an intermediate compound(s) that has antimicrobial properties.

Prevention of infective endocarditis: Guidelines from the American Heart Association: A guideline from the American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group

BACKGROUND The purpose of this statement is to update the recommendations by the American Heart Association (AHA) for the prevention of infective endocarditis, which were last published in 1997. METHODS AND RESULTS A writing group appointed by the AHA for their expertise in prevention and treatment of infective endocarditis (IE) with liaison members representing the American Dental Association, the Infectious Diseases Society of America and the American Academy of Pediatrics. The writing group reviewed input from national and international experts on IE. The recommendations in this document reflect analyses of relevant literature regarding procedure-related bacteremia and IE; in vitro susceptibility data of the most common microorganisms, which cause IE; results of prophylactic studies in animal models of experimental endocarditis; and retrospective and prospective studies of prevention of IE. MEDLINE database searches from 1950 through 2006 were done for English language articles using the following search terms: endocarditis, infective endocarditis, prophylaxis, prevention, antibiotic, antimicrobial, pathogens, organisms, dental, gastrointestinal, genitourinary, streptococcus, enterococcus, staphylococcus, respiratory, dental surgery, pathogenesis, vaccine, immunization and bacteremia. The reference lists of the identified articles were also searched. The writing group also searched the AHA online library. The American College of Cardiology/AHA classification of recommendations and levels of evidence for practice guidelines were used. The article subsequently was reviewed by outside experts not affiliated with the writing group and by the AHA Science Advisory and Coordinating Committee. CONCLUSIONS The major changes in the updated recommendations include the following. (1) The committee concluded that only an extremely small number of cases of IE might be prevented by antibiotic prophylaxis for dental procedures even if such prophylactic therapy were 100 percent effective. (2) IE prophylaxis for dental procedures should be recommended only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from IE. (3) For patients with these underlying cardiac conditions, prophylaxis is recommended for all dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa. (4) Prophylaxis is not recommended based solely on an increased lifetime risk of acquisition of IE. (5) Administration of antibiotics solely to prevent endocarditis is not recommended for patients who undergo a genitourinary or gastrointestinal tract procedure. These changes are intended to define more clearly when IE prophylaxis is or is not recommended and to provide more uniform and consistent global recommendations.

Multicenter collaborative trial of intravenous acyclovir for treatment of mucocutaneous herpes simplex virus infection in the immunocompromised host

Intravenous acyclovir was evaluated in the treatment of 97 immunocompromised patients with mucocutaneous herpes simplex virus infection in a randomized, double-blind, placebo-controlled trial. Acyclovir recipients had significantly shorter periods of virus shedding (p less than 0.0002) and lesion pain (p less than 0.01), and more rapid lesion scabbing (p less than 0.004) and lesion healing (p less than 0.04). The most common adverse reaction was a low incidence of peripheral vein irritation; no serious toxicity could be definitely attributed to acyclovir treatment even in these seriously ill patients. Intravenous acyclovir offers both safe and effective treatment for mucocutaneous herpes simplex virus infection in the immunocompromised host.

Single and multiple pyogenic liver abscesses. Natural history, diagnosis and treatment, with emphasis on percutaneous drainage.

The presenting features, modes of treatment and clinical course were reviewed for 55 patients with pyogenic liver abscess, seen at Duke University Medical Center over a 15-year period. Thirty-three patients had a solitary abscess and 22 had multiple abscesses. Most patients were between the ages of 40 and 60 years. Males predominated, 2.4:1. Major underlying conditions included biliary tract disease, malignancy and colonic disease. Eight patients, each with a solitary abscess, had no identifiable underlying condition. Symptoms and signs were nonspecific: fever, chills, focal abdominal tenderness and hepatomegaly were common. A raised serum alkaline phosphatase level was the most consistent abnormal laboratory finding. CT with contrast enhancement, radioisotope scanning and ultrasonography all accurately defined solitary hepatic abscesses. However, CT scan was more successful than other imaging techniques in detecting multiple abscesses. In seven patients the diagnosis was made only at laparotomy. Overall, a diagnosis of liver abscess was made in 50 living patients (91%). Microorganisms were recovered from pus and/or blood cultures of 44 patients (80%). Most common were enteric gram-negative facultative rods, anaerobic gram-negative rods, and microaerophilic streptococci. Single abscesses were more likely than multiple abscesses to contain more than one organism. All patients received antibiotics; the choice of antibiotic does not appear to be critical provided the regimen has a broad spectrum including activity against anaerobes. Surgical or percutaneous drainage was successful when attempted in all patients with a single abscess, but the outcome was less favorable in those with multiple abscesses. Percutaneous drainage is currently replacing open operative drainage as the method of choice. Overall mortality in patients with single abscesses was 15% (5/33) and in those with multiple abscesses 41% (9/22).

Ceftriaxone Once Daily for Four Weeks Compared with Ceftriaxone Plus Gentamicin Once Daily for Two Weeks for Treatment of Endocarditis Due to Penicillin-Susceptible Streptococci

This randomized, multicenter, open-label study compared the efficacy and safety of monotherapy with 2 g of intravenous ceftriaxone once daily for 4 weeks with those of combination therapy with 2 g of intravenous ceftriaxone and 3 mg of intravenous gentamicin/kg once daily for 2 weeks as therapy for endocarditis due to penicillin-susceptible streptococci. Sixty-one patients were enrolled in the study. Clinical cure was observed for 51 evaluable patients both at termination of therapy and at the 3-month follow-up: 25 (96.2%) of 26 monotherapy recipients and 24 (96%) of 25 combination therapy recipients. Of the 23 patients in each treatment group who were microbiologically evaluable, 22 (95.7%) in each group were considered cured. No patient had evidence of relapse. Fourteen patients (27.5%) required cardiac surgery after initiation of treatment, including five monotherapy recipients and nine combination therapy recipients. Adverse effects were minimal in both treatment groups. We conclude that 2 g of ceftriaxone once daily for 4 weeks and 2 g of ceftriaxone in combination with 3 mg of gentamicin/kg once daily for 2 weeks are both effective and safe for the treatment of streptococcal endocarditis.

Chemotherapy of experimental streptococcal endocarditis. I. Comparison of commonly recommended prophylactic regimens.

The effectiveness of various antibiotics commonly recommended for the prophylaxis of bacterial endocarditis has been evaluated in experimental streptococcal endocarditis in rabbits. High doses of penicillin G did not prevent the development of this infection. The only consistently successful prophylactic regimens using penicillin alone were those which provided for both an early high serum level and more than 9 h of effective antimicrobial action. Vancomycin was the only other drug which proved uniformly successful when given alone, even though the duration of its antimicrobial action in the blood was only 3 h. However, combined therapy using penicillin G or ampicillin with streptomycin was always effective in prophylaxis. Treatment with single injections of ampicillin, cephaloridine, cephalexin, clindamycin, cotrimoxazole, rifampicin, streptomycin, erythromycin, and tetracycline failed to prevent infection. The findings provide information on the effect of antimicrobials in vivo and may be applicable to the chemoprophylaxis of infective endocarditis in clinical practice.

International health and internal medicine residency training: The Duke University experience

OBJECTIVE To evaluate the impact of the Duke University Medicine Residency International Health Program (IHP) on program participants and to evaluate the relationship of the IHP to the residency program. SUBJECTS AND METHODS The Duke University Medicine Residency Program classes of 1988 to 1996 participated in a questionnaire-based survey. All program participants (n = 59), a group of nonparticipants (n = 138), and residents who had not yet had an opportunity to participate (preparticipants; n = 106). RESULTS The overall response rate to the questionnaire was 93%. Participation exceeded expectations and had a strongly positive impact on personal and professional lives of the majority of the participants. Participants reported a significant positive impact on their training in internal medicine and their knowledge of tropical medicine. A minority of nonparticipants identified a positive effect in these areas due to conferences and interactions with their participating colleagues. Participants who changes career plans during residency tended to move toward areas of general internal medicine or public health, in contrast to nonparticipants who tended to change areas of subspecialty or chose private practice. The IHP was identified as a significant factor for selection of the Duke Medicine Residency by 42% of the preparticipant group. Nearly all of the respondents (99%) indicated that the IHP should be continued. CONCLUSION The IHP has a measurable positive impact on the participants, as well as on the Medicine Residency Program.

Chemotherapy of experimental streptococcal endocarditis. II. Synergism between penicillin and streptomycin against penicillin-sensitive streptococci.

Bacterial endocarditis was produced by intravenous injection of Streptococcus viridans into rabbits with preexisting sterile endocardial vegetations. After 6 h had elapsed, bacteria in the vegetations could not be eradicated by brief treatment with antimicrobials to which the streptococci were sensitive. However, when treatment with penicillin was continued for 4 days, the animals were cured. The 6-h infection therefore offered a model in which treatments could be conveniently compared over a short period. Synergism was demonstrated between penicillin and streptomycin in endocarditis due to a fully penicillin-sensitive streptococcus, a point which had not been previously proved in vivo. The clinical implications are discussed.

Diagnostic methods: Current best practices and guidelines for histologic evaluation in infective endocarditis

Infective endocarditis (IE) often presents diagnostic and therapeutic challenges and continues to cause high morbidity and mortality. Confirmation of the diagnosis of IE is important for the purposes of epidemiologic and clinical studies and is crucial for patient management. Despite recent advances in diagnostic techniques, about 10% of IE cases remain culture-negative. Because pathological examination of cardiac valves to demonstrate vegetations and valvular inflammation remains the gold standard for the diagnosis of IE, the role of the pathologist is often decisive, especially when bacteriologists fail to isolate a microorganism or when a microorganism that has been isolated may be a contaminant. Furthermore, the pathologist may play an important role in identification of previously unknown infectious agents.

The cost effectiveness of antiretroviral treatment strategies in resource-limited settings.

Background:Optimal resource allocation for antiretroviral treatment (ART) in developing countries requires assessment of different strategies for drug treatment and laboratory monitoring. Objectives:To compare costs and outcomes for 10 000 simulated HIV-infected patients followed every 6 months for 10 years in a limited-resource setting. Method:Five nested strategies, with and without the availability of a second-line treatment regimen, were simulated: (a) no ART (NO ART); (b) with ART but without any laboratory markers of HIV other than positive serology (ART ONLY); (c) ART plus total lymphocyte count (TLC); (d) ART plus CD4 cell counts (CD4); and (e) ART plus CD4 cell count plus viral load measurement (VL). Baseline prices of CD4 cell count and viral load measurements were